Ischemic heart disease, the underlying cause of most acute myocardial infarctions, congestive heart failure, arrhythmias, and sudden cardiac death, is the leading cause of morbidity and mortality in all industrialized nations. In the United States, ischemic heart disease causes nearly 20% of all deaths (˜600 000 deaths each year). An estimated 1.1 million Americans will have a new or recurrent acute myocardial infarction this year, and many survivors will experience lasting morbidity, with progression to heart failure and death. As the population grows older and co morbidities such as obesity and diabetes become more prevalent, the enormous public health burden caused by ischemic heart disease is likely to increase even further (Bolli, et al., Circ. Res. 95:125-134, 2004).
Thrombopoietin (Tpo) is a protein found in the body that stimulates the bone marrow to produce platelets and help in their development. Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is a truncated protein (163 amino acids) containing only the receptor-binding region, which has been chemically modified (N terminal reductive alkylation) by the addition of PEG; PEG-rHuMGDF was developed by Amgen. PEGylation of Tpo further increases the plasma half-life by 10-fold. Both forms of Tpo have undergone extensive clinical investigation, and the biologic activities of both of these proteins are similar. Both have been shown to be potent stimulators of megakaryocyte growth and platelet production and are biologically active in reducing the thrombocytopenia of non-myeloablative chemotherapy. Following systemic administration, the platelet count begins to increase after three to five days.
It would be desirable to provide a therapy and therapeutic products to effectively increase resistance of the heart to injury caused by ischemia, including in the setting of cardiac surgery and transplantation (global myocardial ischemia) and heart attack (regional myocardial ischemia).